Programmed cell death (PCD) is an essential part of development, and is used, among other things, to sculpt organs and to discard cells whose functions are no longer required. Although global regulators of PCD have been well characterized, little is known about cell-specific signals that regulate PCD during development. Our long-term goal is to identify and characterize cell-specific developmental signals that impinge on the global PCD machinery to regulate a cell's survival or demise. C. elegans is an excellent organism for studying regulation of PCD. Studies in this organism identified genes (ced-3, ced-4, and ced-9) that define a core pathway controlling virtually all PCD. Homologs of these genes (caspase proteases, Apaf- 1, and Bcl-2 family members, respectively) can function in a similar pathway in mammals. To understand how this pathway is regulated in specific C. elegans cells we will pursue two main objectives: 1) We will perform genetic screens to identify genes regulating PCD of the male-specific CEM neurons and PCD of the embryonic tail-spike cells. While CEM PCD is likely to be controlled by cell-autonomous processes, PCD of the tail-spike cells may be controlled by a signaling cascade that induces transcription of the core PCD gene ced-3. We have already identified two genes, cdr-1 and cdr-2, that prevent CEM death in hermaphrodites. Their roles in CEM PCD will be explored. 2) We will define the role of the CED-9-interacting protein CIP-l in PCD in the male tail. CIP- 1, a BH3 -domain protein, promotes PCD when over-expressed and is exclusively transcribed in the developing male tail. We will generate mutations in the gene, define residues essential for its function, and study its intracellular localization. Misregulation of PCD is a hallmark of many disease states in humans. For example, excess PCD is observed in several neurodegenerative diseases, and lack of PCD is seen in cancer. The remarkable conservation of the PCD machinery between C. elegans and humans strongly suggests that our studies will yield insight into how human PCD is regulated as well.